CN1871234B - 2-amino-4-heteroarylethyl thiazoline derivatives and their use as inhibitors of inducible NO-synthase - Google Patents
2-amino-4-heteroarylethyl thiazoline derivatives and their use as inhibitors of inducible NO-synthase Download PDFInfo
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Abstract
The present invention relates to the use of 2-amino-4-heteroarylethyl-thiazoline derivatives of formula (I) in which Het represents a thienyl, pyrimidyl, pyridyl or thiazolyl radical or pharmaceutically acceptable salts thereof as inhibitors of inducible NO-synthase.
Description
The present invention relates to the 2-amino-4-heteroaryl ethyl-thiazoline derivatives of formula (I) or its pharmacy acceptable salt purposes as inducible NO-synthase inhibitors,
Theme of the present invention is the 2-amino-4-heteroaryl ethyl-thiazoline derivatives and the purposes of its pharmacy acceptable salt in pharmaceutical compositions of formula (I), and described composition is used for prevention and treatment wherein relates to the disease that predisposition is sent out inducible NO-synthase (NOS-2 or iNOS) and caused the unusual generation of nitrogen protoxide (NO); The pharmaceutical composition that contains novel 2-amino-4-heteroaryl ethyl-thiazoline derivatives and pharmacy acceptable salt thereof; And novel 2-amino-4-heteroaryl ethyl-thiazoline derivatives and pharmacy acceptable salt thereof.
Nitrogen protoxide (NO) is the dispersion pattern group relevant with pathologic process with multiple physiology, it synthesizes by oxidation L-arginine, this reaction is by the gang's enzyme catalysis that is called nitricoxide synthase or NO-synthase (NOS), and its international enzyme nomenclature is numbered E.C.1.14.13.39.
Known three kinds of NOS isozymes, wherein two kinds is composing type, a kind of is induction type:
-neuron NOS (NOS-1 or nNOS) separates and duplicates from nervous tissue at first, and it is constitutive enzyme in described nervous tissue.NOS-1 produces NO according to based on the mechanism of calcium and calmodulin various physiological stimulations such as membrane receptor being activated to react.
-induced NOS (NOS-2 or iNOS) can be made a response as the cytokine in the various cells for example or bacterial antigens and induced immunostimulation, these cells are as for example scavenger cell, endotheliocyte, liver cell, neurogliocyte, and the cell of many other types.The activity of these isozymes is not subjected to the adjusting of calcium, therefore once inducing, will produce a large amount of NO in the time that prolongs.
-Nei integumentary pattern NOS (NOS-3 or eNOS) belongs to calcium and calmodulin-dependent constitutive enzyme.This NOS confirms in vascular endothelial cell at first, and wherein, it activates physiological stimulation such as membrane receptor and reacts and produce NO.
Relevant with intercellular signal transfer functions usually by the NO that neuron pattern and interior integumentary pattern composing type isozyme (NOS-1 and NOS-3) produce.For example: the endotheliocyte on the blood vessel is induced following smooth muscle cell diastole by producing NO, thereby helps to regulate arterial pressure.
A large amount of NO that produce relate in particular to the pathological phenomenon relevant with the acute and chronic inflammation process of multiple tissue and organ by induced NOS-2 isozyme.
Thus, predisposition is led NOS-2 and is too much produced NO and bring into play certain effect in the nervous system degeneration pathology, and these pathologies are as multiple sclerosis for example, focal or global brain ischemia, brain or spinal cord injuries receptor, Parkinson's disease, Huntington Chorea, Alzheimer, amyotrophic lateral sclerosis, migraine, dysthymia disorders, schizophrenia, anxiety disorder, epileptics.Similarly, except that central nervous system, inducing of NOS-2 also relates to multiple pathology with inflammatory factor, as for example diabetes, atherosclerosis, myocarditis, sacroiliitis, joint disease, asthma, irritable bowel syndrome, Crohn disease, peritonitis, gastroesophageal reflux, uveitis, Ji-Ba syndrome, glomerulonephritis, lupus erythematosus and psoriatic.NOS-2 also relates to the tumor growth of some form, as for example epithelioma, gland cancer or sarcoma, and relates in Gram-positive or the gram-negative cells or the extracellular infectation of bacteria.
The all situations that too much produces NO all is deleterious, should be desirable by using the generation that the material that can suppress NOS-2 reduces NO therefore.Yet the important physiological action of being brought into play in view of composing type isozyme NOS-3, particularly in the effect of regulating aspect the arterial pressure must reduce the influence to isozyme NOS-3 as far as possible when suppressing isozyme NOS-2.In fact, knownly use non-selective NOS isozyme inhibitor and can cause vasoconstriction and the arterial pressure (Moncada that rises, S., Palmer, R.M.J. and Higgs, E.A., " from L-arginine biosynthesizing nitrogen protoxide: a kind of approach of regulating cell function and communication ", Biochem.Pharmacol., 1989,38:1709-1715).These influences to cardiovascular systems are deleterious, because can reduce the nutrient supply to tissue.Therefore, the present invention relates to the NOS-2 restraining effect is significantly higher than the inhibiting compound to NOS-3.
Nos inhibitor based on thiazoline is addressed in patent application WO94/12165, WO95/11231 and WO96/14842 especially.
2-amino-4-heteroaryl ethyl-the thiazoline derivatives that the present invention relates to formula (I) is used for preventing or treating the purposes of the useful medicine of disease in preparation, described disease relates to that predisposition is sent out inducible NO-synthase (NOS-2 or iNOS) and the nitrogen protoxide (NO) that causes is unusual produces, and wherein Het represents 2-thienyl, 3-thienyl, 2-pyrimidyl, 5-pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.
Formula (I) compound contains one or more asymmetric carbons, so it can be racemic form or enantiomer and diastereomeric form, and these compounds and composition thereof also constitute a part of the present invention.
In addition, formula (I) compound can be tautomeric form (Ia):
These tautomeric forms also constitute a part of the present invention.
In useful formula (I) compound, can mention following compound according to the present invention:
4-(2-pyridine-2-base ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine,
4-(2-pyridin-3-yl ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine,
4-(2-pyridin-4-yl ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine,
4-(2-thiene-3-yl-ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine,
Its racemic mixture, enantiomer, diastereomer, tautomer, with and pharmacy acceptable salt, more particularly following compound:
(+)-(4R)-4-(2-pyridine-2-base ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine,
(+)-(4R)-4-(2-pyridin-3-yl ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine,
(+)-(4R)-4-(2-pyridin-4-yl ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine,
(4R)-and 4-(2-thiene-3-yl-ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine,
Its tautomer with and pharmacy acceptable salt.
In useful and particularly preferred formula (I) compound, can mention following compound according to the present invention:
4-(2-thiene-3-yl-ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine,
Its racemoid, enantiomer, tautomer, with and pharmacy acceptable salt.
The invention still further relates to pharmaceutical composition, it contains formula (I) derivative as activeconstituents, wherein Het represents 2-thienyl, 3-thienyl, 2-pyrimidyl, 5-pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl, with and racemic mixture, enantiomer, diastereomer and composition thereof, its tautomer and its pharmacy acceptable salt.
Formula (I) compound can be by preparing the cyclisation of formula (II) derivative,
Wherein Het have with formula (I) in identical implication.
This cyclisation usually under about 100 ℃ temperature, in water medium, use sour example hydrochloric acid to carry out.Usually use 6N hydrochloric acid.
Formula (II) derivative can obtain according to following reaction scheme:
In these general formulas; Het have with formula (I) in identical implication; Ra is the amine functions blocking group; as those T.W.GREENE, " protecting group in the organic synthesis ", the protecting group described in the J.Wiley-IntersciencePublication (1991); and Rb is a beta-alkamine function and protecting group; as those T.W.GREENE, " protecting group in the organic synthesis ", the protecting group described in the J.Wiley-IntersciencePublication (1991).Preferably, the amine functions blocking group is ethanoyl or tertbutyloxycarbonyl, and beta-alkamine function and protecting group is isopropylidene or benzal base.X represents halogen atom, preferred bromine or iodine, or perfluoro alkyl sulfonic acid base.
Reaction a usually at 10 ℃ to the temperature between the reaction medium boiling point, in aromatic solvent such as toluene or ether solvents such as THF, in the presence of boron derivative such as 9-boron bicyclononane or two (3-methyl-2-butyl) borine (disiamylborane), carry out.Then, in reaction medium, add the aqueous solution of alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, add transition metal complex such as tetrakis triphenylphosphine palladium or diphenylphosphino ferrocenyl palladium chloride then, add Het-X then.Under the reaction medium boiling temperature, heating gained mixture.
Wherein Ra is that amine functions blocking group and Rb are that the deprotection reaction b of the compound of beta-alkamine function and protecting group is undertaken by any deprotection method well known by persons skilled in the art; those T.W.GREENE particularly; " protecting group in the organic synthesis ", the method described in the J.Wiley-IntersciencePublication (1991).Preferably, if the amine functions blocking group is that tertbutyloxycarbonyl and beta-alkamine function and protecting group are isopropylidene or benzal base, then this is reflected at and uses sour example hydrochloric acid to carry out in aqueous medium under about 25 ℃ temperature.Usually use 6N hydrochloric acid.If the amine functions blocking group is that ethanoyl and beta-alkamine function and protecting group are isopropylidene or benzal base, then this is reflected under about reaction medium boiling temperature, uses sour example hydrochloric acid to carry out in aqueous medium.Usually use 6N hydrochloric acid.
The reaction c 20 ℃ to the temperature between the reaction medium boiling point, at inert solvent as (C
1-4) in the Fatty Alcohol(C12-C14 and C12-C18) (particular methanol or ethanol), in the presence of tertiary amine such as triethylamine, undertaken by the effect of tert.-butyl isothiocyanate.
Separate type (I) compound, and can carry out purifying by conventional currently known methods, for example crystallization, chromatography or extraction.
The enantiomer of formula (I) compound can obtain by resolving racemic mixtures, for example according to people such as PIRCKLE W.H., " asymmetric synthesis ", the 1st volume, chiral column chromatography among the Academic Press (1983) is carried out, perhaps by forming salt or synthetic from chiral precurser.Its diastereomer can be according to known ordinary method (crystallization, chromatography or from chiral precurser) preparation.
Can choose wantonly by mineral acid or organic acid effect at organic solvent formula (I) compound is converted into mineral acid or organic acid additive salt as alcohol, ketone, ether or chlorinated solvent.These salt also constitute a part of the present invention.
The example of the pharmacy acceptable salt that can mention has: benzene sulfonate, hydrobromate, hydrochloride, Citrate trianion, esilate, fumarate, gluconate, iodate, isethionate, maleate, mesylate, methylene-bis-2-Naphthol hydrochlorate (methylenebis-β-oxynaphthoate), nitrate, oxalate, embonate, phosphoric acid salt, salicylate, succinate, vitriol, tartrate, cariamyl (theophyllinacetate) and tosilate.
Formula (I) compound is the inhibitor of inducible NO-synthase or 2 type NO-synthase (NOS-2), therefore can be used for preventing and treatment and the too much relevant disease of NO generation, as multiple sclerosis, focal or global brain ischemia, brain or spinal cord injuries receptor, Parkinson's disease, Huntington Chorea, Alzheimer, amyotrophic lateral sclerosis, migraine, dysthymia disorders, schizophrenia, anxiety disorder, epileptics, diabetes, atherosclerosis, myocarditis, sacroiliitis, joint disease, asthma, irritable bowel syndrome, Crohn disease, peritonitis, gastroesophageal reflux, uveitis, Ji-Ba syndrome, glomerulonephritis, lupus erythematosus and psoriatic, the tumour of some form is as for example epithelioma, the growth of gland cancer or sarcoma, and in Gram-positive or the gram-negative cells or the infectation of bacteria of extracellular.
These compounds as the activity of NOS-2 and NOS-3 inhibitor be by measure [
3H]-the L-arginine be converted into [
3H]-transformation efficiency of L-citrulline determines, adopts the NOS-2 enzyme fraction and the reorganization ox NOS-3 commercial preparation of extracting in the rat of lipopolysaccharides pre-treatment (organizing preceding 6 hours i.p.10mg/kg in collection) or mouse lung respectively.Under 37 ℃ with compound incubation 20 to 30 minutes in the HEPES damping fluid (50mM, pH 6.7), exist in the described damping fluid 5 μ M (when measuring N OS-2 is active) or 10 μ M (when measuring N OS-3 is active) [
3H]-L-arginine, 1mM NADPH, 15 μ M tetrahydrobiopterins (tetrabiopterine), 1 μ M FAD, 0.1mM DTT, also contain 10 μ g/ml calmodulins and 1.25mM CaCl when active when measuring NOS-3
2Add the cold HEPES damping fluid (100mM, pH 5.5) that contains 10mM EGTA and end incubation, and add the cationic ion exchange resin of 500mg (AG50W-X8, gegenion: Na
+) with from [
3H]-separate in the L-citrulline [
3H]-the L-arginine.Place made in 5 minutes respectively be separated after, in the presence of suitable scintillation solution, measure the radioactivity that keeps in the liquid phase with scintillometer.Use L-[urea groups-
14C]-citrulline is as external standard, can estimate formed L-[
3H]-rate of recovery of citrulline.
The activity of NOS-2 or NOS-3 with the every milligram of albumen per minute that contains in the reaction medium formed [
3H]-the picomole numerical table of L-citrulline shows.
In this test that the NOS-2 enzyme is carried out, the IC of formula (I) compound
50Value is less than or equal to 10 μ M.
Selectivity is to pass through IC
50NOS-3/IC
50The ratio measurement of NOS-2, the selectivity of compound is greater than 45.
Formula (I) compound is hypotoxic, the LD that it records in mouse through the skin approach
50Greater than 40mg/kg.
Following example has illustrated the present invention, but does not comprise full content.
Embodiment 1:
(4R)-and 4-(2-thiene-3-yl--ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine hydrochlorate
With 0.72g N-(tertiary butyl)-N '-[(1R)-2-hydroxyl-1-(2-thiene-3-yl--ethyl) ethyl]-thiocarbamide at 20cm
3Mixture in the 5N aqueous hydrochloric acid heated 18 hours under about 100 ℃ temperature is held concurrently the magnetic agitation condition, and evaporation reaction medium under about 40 ℃ temperature is held concurrently decompression (2kPa) condition is used 20cm then
3Ethanol Treatment gained resistates is also concentrated once more according to above-mentioned condition.Use 5cm
3Ethanol Treatment gained evaporation residue filters, and uses 2cm
3Washing with alcohol twice is used 5cm again
3The ether washed twice.Product is dry under about 20 ℃ temperature is held concurrently vacuum (10Pa) condition in baking oven.Obtain about 0.28g (4R)-4-(2-thiene-3-yl-ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine hydrochlorate is the beige solid form, and molten point is 150 ℃.[
1H NMR composes (300MHz, (CD
3)
2SO d6, δ (ppm)): from 1.85 to 2.10 (mt:2H); 2.70 (mt:2H); From 3.30 to 3.45 (mt:1H); (3.69 dd, J=11 and 7.5Hz:1H); 4.21 (mt:1H); (7.05 dd, J=5 and 1.5Hz:1H); 7.26 (mt:1H); (7.50 dd, J=5 and 3Hz:1H); 9.10 (mf:1H); 9.61 (mf:1H); 10.27 (s is big: 1H)].
N-(tertiary butyl)-N '-[(1R)-2-hydroxyl-1-(2-thiene-3-yl-ethyl) ethyl]-thiocarbamide
Under about 20 ℃ temperature, with the 40cm of 1.2g (2R)-2-amino-4-(3-thienyl)-1-Kauri-butanol hydrochloric salt
3Ethanolic soln, 1.1cm
3Tert.-butyl isothiocyanate and 1cm
3Triethylamine stirs at the inert atmosphere lower magnetic force, heats 20 hours under about 50 ℃ temperature then.Concentrated reaction medium under about 50 ℃ temperature is held concurrently decompression (2kPa) condition then.Evaporation residue is used silicagel column (particle diameter 60-200 μ m, diameter 3.6cm, high 20cm) chromatography purification down at argon pressure (70kPa),, obtain 30cm with cyclohexane/ethyl acetate mixture (volume ratio is 60/40) wash-out
3Fraction.Collection contains expects the fraction of product and evaporating under about 40 ℃ temperature is held concurrently decompression (2kPa) condition.Obtain about 0.73g N-(tertiary butyl)-N '-[(1R)-2-hydroxyl-1-(2-thiene-3-yl-ethyl) ethyl]-thiocarbamide, be the form of water white oil.[
1H NMR composes (300MHz, (CD
3)
2SO d6, δ (ppm)): 1.42 (s:9H); From 1.60 to 1.95 (mt:2H); 2.60 (t is big, J=8Hz:2H); 3.38 (mt:1H); 3.50 (mt:1H); 4.26 (mf:1H); 4.80 (mf:1H); (7.01 dd, J=5 and 1.5Hz:1H); From 7.15 to 7.25 (mt:2H); 7.20 (s:1H); (7.46 dd, J=5 and 3Hz:1H)].
(2R)-2-amino-4-(3-thienyl)-1-Kauri-butanol hydrochloric salt
Under about 20 ℃ temperature, with 1.8g 2,2-dimethyl-4-(2-thiene-3-yl--ethyl)-oxazolidines-3-t-butyl formate is at 5cm
35N aqueous hydrochloric acid and 5cm
3Suspension in the dioxane stirred 3 hours.Concentrated reaction mixture under about 40 ℃ temperature is held concurrently decompression (2kPa) condition then.Obtain about 1.3g viscous crude shape (2R)-2-amino-4-(3-thienyl)-1-Kauri-butanol hydrochloric salt.[
1H NMR composes (300MHz, (CD
3)
2SO d6, δ (ppm)): from 1.70 to 1.95 (mt:2H); 2.70 (t is big, J=8Hz:2H); 3.05 (mt:1H); (3.50 dd, J=11 and 6Hz:1H); (3.64 dd, J=11 and 4Hz:1H); (7.02 dd, J=5 and 1.5Hz:1H); 7.23 (d is big, J=3Hz:1H); (7.49 dd, J=5 and 3Hz:1H); 8.02 (mf:3H)].
(4R)-2,2-dimethyl-4-(2-thiene-3-yl--ethyl)-oxazolidines-3-t-butyl formate
Under inert atmosphere, stirring, will about 26.4cm
39-boron two ring-[3.3.1]-nonane solution add 1.5g (4R)-2, and 2-dimethyl-4-vinyl-oxazolidines-3-t-butyl formate is at 33cm
3In the suspension in the toluene.Under about 70 ℃ temperature, reaction medium was heated 30 minutes.Suspend heating, add 5.3cm
35N aqueous sodium hydroxide solution and 2cm
3Water after 1 minute, adds 0.23g tetrakis triphenylphosphine palladium (0) and 0.81cm again
33 bromo thiophene.Under about 90 ℃ temperature, continue heating 22 hours.After reaction mixture under about 20 ℃ temperature, add 100cm
3Ethyl acetate.Place organic phase,, filter, and under about 40 ℃ temperature is held concurrently decompression (2kPa) condition, concentrate through dried over mgso.Evaporation residue down with silicagel column (particle diameter 60-200 μ m, diameter 3.6cm, high 30cm) chromatography purification, with cyclohexane/ethyl acetate mixture (volume ratio is 90/10) wash-out, obtains 60cm at argon pressure (70kPa)
3Fraction.Merge to contain and expect the fraction of product and concentrated under about 40 ℃ temperature is held concurrently decompression (2kPa) condition.Obtain (4R)-2 of about 1.8g yellow oily, 2-dimethyl-4-(2-thiene-3-yl--ethyl)-oxazolidines-3-t-butyl formate.[
1H NMR composes (400MHz, (CD
3)
2SO d6, temperature 373K, δ (ppm)): 1.45 (s:9H); 1.54 (s:6H); From 1.75 to 2.10 (mt:2H); 2.65 (mt:2H); (3.75 dd, J=9 and 2Hz:1H); 3.85 (mt:1H); (3.94 dd, J=9 and 6Hz:1H); 6.99 (d is big, J=5Hz:1H); 7.14 (mt:1H); (7.40 dd, J=5 and 3Hz:1H)].
Pharmaceutical composition of the present invention is made up of with the pure substance form or with the product blended composition forms that can be inertia or physiologically active compatible with any other pharmacy the isomer of formula (I) compound or this compound or tautomer or salt.But medicine oral administration of the present invention, through parenteral, per rectum or local the use.
Operablely be used for Orally administered solids composition and comprise tablet, pill, pulvis (gelatine capsule agent, cachet) or granule.In these compositions, effective constituent of the present invention is mixed with one or more inert diluents such as starch, Mierocrystalline cellulose, sucrose, lactose or silicon-dioxide under argon gas stream.These compositions also can comprise the material except that thinner, for example one or more lubricants such as Magnesium Stearate or talcum powder, dyestuff, dressing thing (sugar-coat) or gloss-imparting agent.
Operablely be used for Orally administered liquid composition and comprise pharmaceutically acceptable solution, suspensoid, emulsion, syrup and elixir, contain inert diluent such as water, ethanol, glycerine, vegetables oil or liquid paraffin.These compositions also can comprise the material except that thinner, for example moist products, sweeting agent, thickening material, seasonings or stablizer.
The aseptic composite that is used for parenteral administration is water-based or non-aqueous solution agent, suspensoid or emulsion preferably.Spendable solvent or vehicle comprise for example ethyl oleate of water, propylene glycol, polyoxyethylene glycol, vegetables oil, particularly sweet oil, injectable organic ester, or other suitable organic solvent.These compositions also can comprise auxiliary, particularly wetting agent, isotonic agent, emulsifying agent, dispersion agent and stablizer.Sterilization can be carried out in several modes, for example by sterile filtration, in composition, add disinfectant, carry out by radiation or by heating.They also can be made into the aseptic solid composite form, and it dissolves in sterilized water or any other injectable sterile media when using.
The composition that is used for rectal administration is suppository or rectum capsule, and it also contains vehicle such as theobroma oil, semi-synthetic glyceryl ester or polyoxyethylene glycol except containing active result.
Be used for topical application of compositions and can be for example ointment, lotion, eye drops, mouth wash shua, nasal drop or aerosol.
In the treatment to human diseases, compound of the present invention is particularly useful for treating and/or preventing multiple sclerosis, focal or global brain ischemia, brain or spinal cord injuries receptor, Parkinson's disease, Huntington Chorea, Alzheimer, amyotrophic lateral sclerosis, migraine, dysthymia disorders, schizophrenia, anxiety disorder, epileptics, diabetes, atherosclerosis, myocarditis, sacroiliitis, joint disease, asthma, irritable bowel syndrome, Crohn disease, peritonitis, gastroesophageal reflux, uveitis, Ji-Ba syndrome, glomerulonephritis, lupus erythematosus, psoriatic, the tumour of some form is as for example epithelioma, the growth of gland cancer or sarcoma, and in Gram-positive or the gram-negative cells or the infectation of bacteria of extracellular.
Dosage depends on required effect, treatment time length and employed route of administration; Usually one day oral dose of adult is 1mg to 100mg, and unitary dose contains 0.5mg to 50mg active substance.
Following example has been illustrated composition of the present invention:
Embodiment A
Make the gel capsule that contains the 50mg active result and have following composition according to routine techniques:
-Shi (I) compound ... ... ... ... ... ... ... ... ... .50mg
-Mierocrystalline cellulose ... ... ... ... ... ... ... ... ... ... 18mg
-lactose ... ... ... ... ... ... ... ... ... ... ..55mg
-colloidal silica ... ... ... ... ... ... ... ... ... 1mg
-sodium starch glycolate ... ... ... ... ... ... ... ... ... 10mg
-talcum powder ... ... ... ... ... ... ... ... ... ... 10mg
-Magnesium Stearate ... ... ... ... ... ... ... ... ... .1mg
Embodiment B
Make the tablet that contains the 50mg active result and have following composition according to routine techniques:
-Shi (I) compound ... ... ... ... ... ... ... ... ... .50mg
-lactose ... ... ... ... ... ... ... ... ... ... ..104mg
-Mierocrystalline cellulose ... ... ... ... ... ... ... ... ... ... 40mg
-polyvidone ... ... ... ... ... ... ... ... ... ... 10mg
-sodium starch glycolate ... ... ... ... ... ... ... ... ... 22mg
-talcum powder ... ... ... ... ... ... ... ... ... ... 10mg
-Magnesium Stearate ... ... ... ... ... ... ... ... ... .2mg
-colloidal silica ... ... ... ... ... ... ... ... ... 2mg
-Walocel MT 20.000PV, glycerine, titanium dioxide blends (72/3.5/24.5) are in right amount
The weight of 1 film coating of tablets finished tablet is 245mg.
Embodiment C
Contain the 10mg active result and have the injection liquid of following composition:
-Shi (I) compound ... ... ... ... ... ... ... ... ..10mg
-phenylformic acid ... ... ... ... ... ... ... ... ... .80mg
-benzylalcohol ... ... ... ... ... ... ... ... ... ... 0.06ml
-Sodium Benzoate ... ... ... ... ... ... ... ... ... ..80mg
-95% ethanol ... ... ... ... ... ... ... ... ... ..0.4ml
-sodium hydroxide ... ... ... ... ... ... ... ... ... ..24mg
-propylene glycol ... ... ... ... ... ... ... ... ... .1.6ml
-water ... ... ... ... ... ... ... ... ... ... an amount of 4ml of ..
The invention still further relates to that prevention and treatment relate to wherein that predisposition is sent out inducible NO-synthase (NOS-2 or iNOS) and the method that causes the unusual disease that generates of nitrogen protoxide (NO), its by use formula (I) compound, its racemic mixture, enantiomer, diastereomer with and composition thereof, its tautomer and its pharmacy acceptable salt carry out.
Claims (11)
1. formula (I) compound,
Wherein Het represents 2-thienyl or 3-thienyl,
Its racemic mixture, enantiomer, diastereomer or its mixture, its tautomer or its pharmacy acceptable salt.
2. the compound of claim 1, its Chinese style (I) compound is selected from following compound:
4-(2-thiene-3-yl-ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine,
Its racemic mixture, enantiomer, diastereomer or its mixture, its tautomer or its pharmacy acceptable salt.
3. claim 1 or 2 compound, its Chinese style (I) compound is selected from following compound:
(4R)-and 4-(2-thiene-3-yl-ethyl)-4,5-dihydro-1,3-thiazoles-2-base amine, its tautomer or its pharmacy acceptable salt.
4. pharmaceutical composition, it contains each the defined compound of claim 1 to 3 that is in the pharmaceutically acceptable medium.
5. each defined compound of claim 1 to 3 is in the purposes of preparation in the medicine, and described medicine is cured property and is applied to treat and relates to wherein that predisposition is sent out inducible NO-synthase and the unusual disease that generates of nitrogen protoxide that causes.
6. the purposes of claim 5, described medicine is cured property and is applied to treat Parkinson's disease.
7. preparation is as the method for the defined formula of claim 1 (I) compound, and it may further comprise the steps: with the cyclisation of formula (II) derivative,
Wherein Het have with claim 1 in identical implication, and optional product is converted into pharmacy acceptable salt.
8. the preparation method of claim 7, cyclisation is wherein carried out under about 100 ℃ temperature, in acidic medium.
9. the preparation method of claim 8, acidic medium wherein is a 6N hydrochloric acid.
Preparation as claim 7 defined and wherein Het have with claim 1 in the method for formula (II) compound of identical implication, it may further comprise the steps:
Under the effect of boron derivative and X-Het, make the reaction of formula (IIa) compound,
Wherein Ra is that amine functions blocking group and Rb are beta-alkamine function and protecting groups, so that acquisition formula (IIb) compound,
Make formula (IIb) compound be subjected to the effect of deprotection agent, so that acquisition formula (IIc) compound,
Make formula (IIc) compound be subjected to the effect of tert.-butyl isothiocyanate, so that acquisition formula (II) compound,
11. the preparation method of claim 10, its Chinese style (II) compound is N-(tertiary butyl)-N '-[(1R)-2-hydroxyl-1-(2-thiene-3-yl-ethyl) ethyl]-thiocarbamide, formula (IIc) compound is (2R)-2-amino-4-(3-thienyl)-1-Kauri-butanol hydrochloric salt, and formula (IIb) compound is (4R)-2,2-dimethyl-4-(2-thiene-3-yl--ethyl)-oxazolidines-3-t-butyl formate.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0114509A FR2832151B1 (en) | 2001-11-09 | 2001-11-09 | USE OF 2-AMINO-4-HETEROARYLETHYL-THIAZOLINE DERIVATIVES AS INDUCTIBLE NO-SYNTHASE INHIBITORS |
| FR01/14509 | 2001-11-09 | ||
| US35297702P | 2002-01-30 | 2002-01-30 | |
| US60/352,977 | 2002-01-30 | ||
| PCT/FR2002/003809 WO2003040142A1 (en) | 2001-11-09 | 2002-11-07 | 2-amino-4-heteroarylethyl thiazoline derivatives and their use an inhibitors of inducible no-synthase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1871234A CN1871234A (en) | 2006-11-29 |
| CN1871234B true CN1871234B (en) | 2010-06-16 |
Family
ID=8869232
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN028245164A Expired - Fee Related CN1871234B (en) | 2001-11-09 | 2002-11-07 | 2-amino-4-heteroarylethyl thiazoline derivatives and their use as inhibitors of inducible NO-synthase |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1871234B (en) |
| AR (1) | AR037509A1 (en) |
| FR (1) | FR2832151B1 (en) |
| ZA (1) | ZA200403400B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0670720A1 (en) * | 1992-11-27 | 1995-09-13 | The Wellcome Foundation Limited | Enzyme inhibitors |
| AU688811B2 (en) * | 1993-10-21 | 1998-03-19 | G.D. Searle & Co. | Amidino derivatives useful as nitric oxide synthase inhibitors |
| AU4149696A (en) * | 1994-11-15 | 1996-06-06 | Merck & Co., Inc. | Substituted heterocycles as inhibitors of nitric oxide synthase |
-
2001
- 2001-11-09 FR FR0114509A patent/FR2832151B1/en not_active Expired - Fee Related
-
2002
- 2002-10-30 AR ARP020104127A patent/AR037509A1/en unknown
- 2002-11-07 CN CN028245164A patent/CN1871234B/en not_active Expired - Fee Related
-
2004
- 2004-05-05 ZA ZA200403400A patent/ZA200403400B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR2832151A1 (en) | 2003-05-16 |
| FR2832151B1 (en) | 2004-12-17 |
| ZA200403400B (en) | 2005-01-20 |
| CN1871234A (en) | 2006-11-29 |
| AR037509A1 (en) | 2004-11-17 |
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